Deep venous thrombosis (DVT) is a blood clot that has formed in one of the large veins far below the skin and blocks normal blood flow back to the heart. One of the major dangers of DVT is that part of the clot may break off and travel to the heart and lungs promoting a pulmonary embolism (PE). There are approximately 5 million cases of DVT per year in United States with 600,000 cases of PE. Generation of DVT is strongly correlated with the function of factor V, a protein cofactor for prothrombinase. Prothrombinase is the enzymatic complex responsible for thrombin generation. Prothrombinase is composed of the protein cofactor, factor Va, and the enzyme, factor Xa, associated on a cell surface in the presence of divalent metal ions. Incorporation of factor Va into prothrombinase and its interaction with factor Xa results in a 300,000-fold acceleration of the catalytic efficiency of the enzyme as compared to the catalysis of the reaction by factor Xa alone. We have extensive preliminary data which demonstrates that a nonapeptide from the heavy chain of the cofactor possesses a binding region for factor Xa within amino acid region 323-331. Specific aims: (1) We intend to synthesize and develop as drug candidates selective peptidomimetic ligands that functionally inhibit clotting because of the inhibition of the interaction of the cofactor with factor Xa. Inhibition of this interaction will have the same effect as inhibiting thrombin activity directly. (2) Central to this proposal is the use of computer aided drug design and strategic medicinal chemistry approaches to be applied towards the development and refinement of a 3D peptide derived pharmacophore model for the binding of small synthetic peptides to factor Xa. The development of the model will expedite and guide the synthesis of potent new peptidomimetic inhibitors (3) establish inhibitory effects of selected compounds on the direct binding interaction of factor Va with factor Xa and on prothrombinase function. The computer aided drug design, synthesis, and biological evaluation of these new ligands sets the stage for phase II studies in which secondary drug development issues will be addressed.